A headache may be one of several different varieties, each of which has its own unique pain characteristics which differ dramatically. The types of headache include tension, sinus, cluster, rebound and migraine. Migraine is a particularly painful headache that recurs from time to time. The pain is quite severe and often the person with migraine must stay in bed. Dietary, emotional and environmental factors may trigger an attack. On average, migraine sufferers experience an attack per month. Attacks last from four to seventy-two hours. Of interest is that the incidence of migraine appears to be on the rise. Because of the severity and incidence of migraine, prescription medicines have been invented to provide relief.
Migraine sufferers sometimes get a warning signal before the onset of the headache phase of a migraine. The warning signals apparent to the migraineur are classified as aura. The period of aura is preceded by a period classified as prodromal or premonitory period. The periods of aura, prodrome and premonitory are pre-headache. The International Headache Society (IHS) defines aura as neurological symptoms that usually develop over 5–20 minutes and last less than 60 minutes. Headache may occur directly or after an aura free interval of less than 60 minutes. Aura symptoms commonly include, but are not limited to, visual disturbances and numbness or tingling sensations. Less than 20% of patients have migraine with aura (IHS 1.2). See Headache Classification Committee of the International Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia (1988); 8: (Supp. 7): 1–96.
The IHS has defined prodromal symptoms as non-aura symptoms signaling the onset of a migraine attack. The symptoms typically occur a few hours to 48 hours before the onset of the headache phase of the migraine. Headache phase of migraine as used herein means the point in time when head pain is perceived by the sufferer. Prodrome or premonitory symptoms may occur in migraine with (IHS 1.1) and migraine without aura (IHS 1.2). The IHS prefers the term premonitory symptoms over prodrome due to historical use of prodrome to describe aura. Prodrome symptoms as used herein is synonymous to premonitory symptoms. See Headache Classification Committee of the International Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia (1988); 8: (Supp. 7): 1–96.
Prodrome or premonitory symptoms may have physical and mental components. The symptoms have been classified by clinical presentation as excitatory and inhibitory symptoms. Excitatory symptoms include, but are not limited to, irritability, euphoria (being ‘high’), physical hyperactivity, excessive yawning, excessive sleepiness, increased sensitivity to light and sound, and craving for foods. Inhibitory symptoms include, but are not limited to, depression, mental withdrawal, behaviour sluggishness, feeling tired, poor concentration, muscle weakness, anorexia and fluid retention. See Headache Classification Committee of the International Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia (1988); 8: (Supp. 7): 1–96 and Anthony M, Rasmussen B K. In: Olesen J, Tfelt-Hansen P, Welch K M A (eds). The Headaches. New York: Raven Press, Ltd, 1993: 256–257. Prodrome/premonitory symptoms have been estimated to occur in up to 88% of migraine patients. See supra, Rasmussen.
5-HT1 receptor agonists have been found useful in the treatment of migraine. 5-HT1 receptors are located, for example, in the dog saphenous vein and the 5HT1 receptor agonists with which the present invention is concerned contract the dog saphenous vein. Such compounds may therefore be identified by their contractile effect on the dog isolated saphenous vein strip as described, for example, by Apperley et al, Br. J. Pharmacol, 68, 215–224 (1980). Compounds which are selective 5HT1 receptor agonists have also been found to selectively constrict the carotid arterial bed of the anaesthetized dog.
Much work has been done in attempts to identify the subclasses of 5HT1 receptors which are implicated in migraine. It is currently thought that 5HT1B (formerly 5HT1Dβ), 5HT1D (formerly 5HT1Dα) and 5HT1F receptors are particularly important. Tests in isolated cerebral arteries can be used to determine which of these receptor sub-types mediate the action of 5HT1 agonist compounds, for example as described in Bouchelet, I. et al, Mol. Pharmacol 1996, 50, 219–223.
Some 5HT1 agonists, including 5HT1D and 5HT1F agonists have also been found to inhibit the trigeminal nerve. This can be assessed by measuring plasma protein extravasation in the dura mater following trigeminal nerve stimulation and administration of labeled albumin; active compounds produce inhibition of dural plasma protein extravasation in this model, which is described in Buzzi. M. G and Moskowitz M. A, Br. J. Pharmacol, 1990 99, 202–206.
A variety of compounds have been identified in the art as 5HT1 agonists, for example by selective constriction of the dog isolated saphenous vein or constriction of the carotid arterial bed of the anaesthetized dog. These include indole derivatives such as those disclosed inter alia in: published British Patent Specification Nos. 2082175, 2081717, 2083463, 2124210, 2150932, 2162522, 2168347, 2168973, 2185020, 2186874, 2191488, 2008646, 2289464, 2289465, 2286185; published U.S. Pat. Nos. 5,288,748, 5,317,103, 5,382,592, 5,385,928, 5,387,593, 5,418,236, 5,433,915, 5,451,584, 5,466,688, 5,468,768, 5,519,025, 5,545,644, 5,602,128, 5,618,948, 5,637,611, 5,837,715; published German Patent Specification Nos. 4414113, 4226527; published French Patent Specification Nos. 2699918, 2707294, 2737723; published Japanese Patent Specification Nos. 05320157, 06041071, 07097370, 07109265; published European Patent Specification Nos. 147107, 237678, 242939, 244085, 225726, 254433, 303506, 313397, 354777, 382570, 464558, 506363, 506369, 450238, 451022, 451008, 478954, 438230, 494774, 497512, 501568, 580539, 581538, 586866, 590970, 590971, 603432, 610134, 620222, 620223, 644187, 641787, 645385, 648767, 666258, 668273, 683155, 700905, 703229, 707007, 708102, 712837, 714894, 714896, 729958, 733628, 736525, 747353, 749962, 755932, 768301, 810220; and published International Patent Application Nos. WO92/11013, WO92/11014, WO92/06973, WO93/00086, WO92/13856, WO93/00094, WO91/18897, WO93/00333, WO94/02460, WO94/02477, WO94/03446, WO94/06789, WO94/10171, WO94/11363, WO94/11356, WO94/13620, WO94/14773, WO94/14772, WO94/14771, WO94/14770, WO94/15930, WO94/14779, WO94/18193, WO94/21619, WO94121611, WO94/21610, WO94/20466, WO94/24127, WO94/29293, WO95/01334, WO95/01965, WO95/05383, WO95/05381, WO95/05366, WO95/06636, WO95/11903, WO95/20588, WO95121167, WO95/21166, WO95/28933, WO95/32196, WO96/04274, WO96/04269, WO96/06846, WO96/06638, WO96/09288, WO96/11195, WO96/11930, WO96/11923, WO96/11685, WO96/12721, WO96/12713, WO96/16056, WO96/17842, WO96/17831, WO96/16961, WO96/16949, WO96/23789, WO96/23784, WO96/23785, WO96/24596, WO96/29075, WO96/39133, WO97/41802, WO97/03068, WO97/08159, WO97/11695, WO97/13512, WO97/11946, WO97/11945, WO97/17343, WO97/17338, WO97/17337, WO97/18204, WO97/18203, WO97/18202, WO97/18201, WO97/16446, WO97/19073, WO97/38692, WO97/43281, WO97/42189, WO97/45426, WO95/14004, WO98/12183, WO98/14433, WO98/15545. The compounds disclosed in the aforementioned specifications (hereinafter described as “Y compounds”) are described as being useful in the treatment of migraine and cluster headache. Some are also claimed to be useful in treating tension-type headache.
Specific examples of 5HT1 agonist Y compounds include those indole derivatives often called “triptans” such as the compounds with the generic names: sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, almotriptan and frovatriptan. Other examples of 5HT1 agonist Y compounds include those commonly known as ALX-0646, LY334370, U109291, 1S159 and PNU-142633.
Sumatriptan is marketed inter alia in the U.S. as IMITREX® (sumatriptan succinate) Tablets, IMITREX® (sumatriptan succinate) Injection and IMITREX® (sumatriptan) Nasal Spray. In many other countries sumatriptan products are marketed as IMIGRAN®, rather than IMITREX®.
IMITREX® (sumatriptan succinate) Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. IMITREX® (sumatriptan succinate) Tablets are not approved for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. IMITREX® Tablets contain sumatriptan (as its succinate salt), a selective 5HT1 receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-Nmethyl-indole-5-methanesulfonamide succinate (1:1), and it has the structure shown in formula (I):

The empirical formula is C14H21N3O2S·C4H6O4, representing a molecular weight of 413.5. IMITREX® (sumatriptan succinate) Tablets are, for example, disclosed and/or claimed in U.S. Pat. No. 4,816,470, U.S. Pat. Nos. 5,037,845 and 5,863,559, which are incorporated by reference herein.
IMITREX® (sumatriptan succinate) Injection is indicated for (1) the acute treatment of migraine attacks with or without aura and (2) the acute treatment of cluster headache episodes. IMITREX® (sumatriptan succinate) Injection is not approved for use in the management of hemiplegic or basilar migraine. The name, structural formula, empirical formula and molecular weight of sumatriptan succinate are as hereinbefore described. IMITREX® (sumatriptan succinate) Injection is, for example, disclosed and/or claimed in U.S. Pat. No. 4,816,470 and U.S. Pat. No. 5,037,845, which are incorporated by reference herein.
IMITREX® (sumatriptan) Nasal Spray is indicated for the acute treatment of migraine attacks with or without aura in adults. IMITREX® (sumatriptan) Nasal Spray is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. IMITREX® (sumatriptan) Nasal Spray contains sumatriptan, a selective 5-hydroxytryptamine1 receptor subtype agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide, and it has the structure shown in Formula (II):

The empirical formula is C14H21N3O2S, representing a molecular weight of 295.4. Due to the presence of sulphuric acid in the nasal spray formulation, the hemisulphate salt of sumatriptan is formed in situ. IMITREX® (sumatriptan) Nasal Spray is, for example, disclosed and/or claimed in U.S. Pat. No. 4,816,470, U.S. Pat. No. 5,037,845, U.S. Pat. No. 5,705,520 and U.S. Pat. No. 5,554,639, which are incorporated by reference herein.
Naratriptan is marketed inter alia in the United States as AMERGE® (naratriptan hydrochloride) Tablets. In many other countries, the trade mark NARAMIG® is used instead of AMERGE®. AMERGE® Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. AMERGE® Tablets are not approved for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. AMERGE® (naratriptan hydrochloride) Tablets contain naratriptan as its hydrochloride salt. Naratriptan hydrochloride is a selective 5HT1 receptor subtype agonist. It is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the structure shown in formula (III):

The empirical formula is C17H25N3O2S·HCl, representing a molecular weight of 371.93. AMERGE® (naratriptan hydrochloride) Tablets are, for example, disclosed and/or claimed in U.S. Pat. No. 4,997,841, which is incorporated by reference herein.
Rizatriptan is marketed inter alia in the United States as MAXALT® (rizatriptan benzoate) Tablets and MAXALT-MLT™ (rizatriptan benzoate) Orally Disintegrating Tablets. MAXALT® (rizatriptan benzoate) Tablets and MAXALT-MLT™ (rizatriptan benzoate) Orally Disintegrating Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. MAXALT® (rizatriptan benzoate) Tablets and MAXALT-MLT™ (rizatriptan benzoate) Orally Disintegrating Tablets are not approved for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. MAXALT® (rizatriptan benzoate) Tablets and MAXALT-MLT™ (rizatriptan benzoate) Orally Disintegrating Tablets contain rizatriptan benzoate, a selective 5-HT1B/1D receptor agonist. Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-H-indole-3-ethanamine monobenzoate. Its empirical formula is C15H19N5·C7H6O2, representing a molecular weight of the free base of 269.4. MAXALI® (rizatriptan benzoate) Tablets are, for example, disclosed and/or claimed in U.S. Pat. No. 5,298,520 and U.S. Pat. No. 5,602,162, which are incorporated by reference herein. MAXALT-MLT™ (rizatriptan benzoate) Orally Disintegrating Tablets are, for example, disclosed and/or claimed in U.S. Pat. No. 4,305,502, U.S. Pat. No. 4,371,516, U.S. Pat. No. 4,758,598, U.S. Pat. No. 5,298,520 and U.S. Pat. No. 5,602,162, which are incorporated by reference herein.
Zolmitriptan is marketed inter alia in the United States as ZOMIG™ (zolmitriptan) Tablets. ZOMIG™ (zolmitriptan) Tablets are indicated for the acute treatment of migraine with or without aura in adults. ZOMIG™ (zolmitriptan) Tablets are not approved for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. ZOMIG™ (zolmitriptan) Tablets contain zolmitriptan, which is a selective 5-HT1B/1D receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone. The empirical formula is C16H21N3O2, representing a molecular weight of 287.36. ZOMIG™ (zolmitriptan) Tablets are disclosed and/or claimed in U.S. Pat. No. 5,466,699, which is incorporated by reference herein.
Other 5HT1 agonists in development include eletriptan, frovatriptan, almotriptan, ALX-0646, LY334370, U109291, IS159 and PNU-142633.
The above mentioned anti-migraine agents have not been approved for the prevention of migraine. In fact, the current product label for each of these agents states that they are not intended for prophylactic therapy of migraine, e.g., AMERGE® (naratriptan hydrochloride) Tablets. Clinically, these agents are used at the onset of the headache phase of the migraine, (CMAJ 1997; 156:1273–1287.), and are commonly reserved for the treatment of severe migraine pain. (Silberstein S D, Lipton R B, Goadsby P J (eds). Headache in Clinical Practice. Oxford UK: Isis Medical Media Ltd, 1998, 74–77.) Thus, it would be desirable to provide an anti-migraine agent useful for the prevention of the headache phase of the migraine. It would be further desirable to be able to predict the onset of migraine before the head pain actually occurs and thereby permit the prophylactic administration of medicine.
The Automated Neuropsychological Assessment Metrics (ANAM) is a set of standardized batteries of cognitive tests, modified by neuropsychologists in the U.S. Armed Forces for precise measurement of cognitive processing efficiency of military personnel. The tests assess sustained concentration and attention, mental flexibility, spatial processing, cognitive processing efficiency, mood, arousal/fatigue level, and short-term, long-term and working memory. The ANAM is now in the public domain. The most recent version is ANAM V3.lla/96 which includes the following battery of tests:
1. Subject Demographics Form
2. Stanford Sleepiness or Sleep/Fatigue Scale
3. Mood Scale 2
4. Simple and Two-Choice Reaction Time
5. Sternberg Memory Search Tasks
6. Running Memory Continuous Performance Task
7. Mathematical Processing Task
8. Digit Set Comparison Task
9. Logical Reasoning-Symbolic
10. Tower of Hanoi (Tower Puzzle)
11. Stroop Color/Word Interference
12. Code Substitution (Letter/Symbol Comparison)
13. Code Substitution (Immediate and Delayed Recall)
14. Spatial Processing Task (Simultaneous)
15. Matching to Sample
16. Tapping (Left and Right Index Finger)
17. Modified Orientation and Amnesia Test
It would be desirable to be able to use a subset of these tests to predict the onset of migraine before the head pain actually occurs and thereby permit the prophylactic administration of medicine.
The present invention is directed to meeting one or more of the above-stated desirable objectives.